Correcting glutathione deficiency to restore mitochondrial fat oxidation in aging

纠正谷胱甘肽缺乏症以恢复衰老过程中的线粒体脂肪氧化

• 批准号: 8721304
• 负责人: Rajagopal Viswanath Sekhar
• 金额: $ 32.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721304
• 关键词: Adipocytes; Aging; Amino Acids; Antioxidants; Biopsy; Body Composition; Body Weight; Body fat; Burn injury; Carnitine; Cysteine; DEXA; Data; Defect; Diet; Dietary Supplementation; Double-Blind Method; Eating; Elderly; Enzymes; Erythrocytes; Esterification; Fasting; Fat Body; Fatty Acids; Fatty acid glycerol esters; Food; Genes; Genetic Transcription; Glucose; Glutathione; Glycine; Goals; Hepatic; High Pressure Liquid Chromatography; High Prevalence; Human; Insulin Resistance; Kinetics; Link; Lipids; Lipolysis; Liver; Magnetic Resonance Spectroscopy; Malondialdehyde; Mass Spectrum Analysis; Matched Group; Measurement; Measures; Messenger RNA; Mitochondria; Modeling; Mus; Muscle; Muscle Mitochondria; OGTT; Obesity; Oral; Overweight; Oxidative Stress; Physiological; Placebos; Plasma; Proteins; Protocols documentation; Randomized; Research Design; Scanning; Skeletal Muscle; Supplementation; Testing; Tissues; Transferase; Weight; base; dietary supplements; energy balance; enzyme activity; fatty acid oxidation; feeding; intrahepatic; oxidation; oxidative damage; placebo controlled study; protein expression; repaired; restoration; stable isotope

DESCRIPTION (provided by applicant): Elderly humans have the highest prevalence of being overweight and obese, suggesting a defect in energy balance. Under physiological conditions, the predominant fuel of choice in the fasted state is non-esterified fatty acids (NEFA). However in aging, NEFA oxidation in the fasted state is impaired and there is increased glucose utilization, suggesting a defect in mitochondrial b-oxidation. Mitochondria rely on antioxidants fo protection against oxidative damage, and glutathione (GSH) is the most abundant endogenous antioxidant. In past and ongoing studies, we observed that elderly humans were deficient in GSH and this was associated with a 50% lower fat oxidation and 65% higher plasma NEFA levels compared to younger humans. We found that GSH deficiency in elderly humans occurred due to decreased synthesis, because of decreased availability of the GSH precursor amino acids cysteine and glycine. Supplementing the diet of these elderly subjects with cysteine and glycine for 2-weeks fully restored GSH synthesis and concentrations, and significantly lowered markers of cellular damage due to oxidative stress to levels found in young controls. After GSH restoration, fasted NEFA oxidation increased by 30%, and fasted plasma FFA fell by 36%, suggesting that impaired NEFA oxidation in aging is a reversible defect. To investigate whether GSH deficiency in aging is linked to impaired NEFA oxidation and predisposes to excess accumulation of body and tissue fat, we studied and found that 80-week old mice had significantly lower GSH in skeletal muscle and liver, impaired whole-body NEFA oxidation, and higher total body- and intrahepatic- fat, compared to young 20-week old mice. Supplementing diets of older mice with cysteine and glycine for 6-weeks corrected GSH deficiency in muscle and liver, restored whole-body NEFA oxidation, and lowered total body fat, hepatic fat and body weight. These data suggest that in aging, GSH deficiency predisposes to impaired NEFA oxidation and excess body and tissue fat; correcting GSH deficiency by supplementing cysteine and glycine in the diet restores NEFA oxidation and reverses these defects. This proposal will identify mechanisms linking GSH deficiency to impaired mitochondrial NEFA oxidation in elderly humans, and test a simple, safe, inexpensive therapy based on altering dietary composition by supplementing GSH precursor amino-acids cysteine and glycine to correct GSH deficiency and restore mitochondrial NEFA oxidation. The proposal will also test whether restoration of GSH and NEFA oxidation will result in loss of body fat, intrahepatic fat and intramyocellular fat in elderly humans.

描述（由申请人提供）：老年人超重和肥胖的患病率最高，表明能量平衡存在缺陷。在生理条件下，禁食状态下选择的主要燃料是非酯化脂肪酸（NEFA）。然而，在衰老过程中，空腹状态下的 NEFA 氧化受损，葡萄糖利用率增加，表明线粒体 b 氧化存在缺陷。线粒体依靠抗氧化剂来防止氧化损伤，而谷胱甘肽 (GSH) 是最丰富的内源性抗氧化剂。在过去和正在进行的研究中，我们观察到老年人缺乏 GSH，与年轻人相比，这与脂肪氧化降低 50% 和血浆 NEFA 水平升高 65% 有关。我们发现老年人体内谷胱甘肽缺乏症是由于谷胱甘肽前体氨基酸半胱氨酸和甘氨酸的可用性降低而导致合成减少所致。在这些老年受试者的饮食中补充半胱氨酸和甘氨酸两周，可以完全恢复谷胱甘肽的合成和浓度，并显着地将氧化应激引起的细胞损伤标记物降低到年轻对照组的水平。 GSH恢复后，空腹NEFA氧化增加30%，空腹血浆FFA下降36%，表明衰老过程中NEFA氧化受损是一种可逆的缺陷。为了研究衰老过程中 GSH 缺乏是否与 NEFA 氧化受损以及导致身体和组织脂肪过度积累有关，我们研究发现，与 20 周龄的年轻小鼠相比，80 周龄小鼠骨骼肌和肝脏中的 GSH 显着降低，全身 NEFA 氧化受损，体内和肝内脂肪总量较高。在老年小鼠的饮食中补充半胱氨酸和甘氨酸 6 周，可以纠正肌肉和肝脏中的 GSH 缺乏，恢复全身 NEFA 氧化，并降低全身脂肪、肝脂肪和体重。这些数据表明，在衰老过程中，GSH 缺乏容易导致 NEFA 氧化受损以及身体和组织脂肪过多。通过在饮食中补充半胱氨酸和甘氨酸来纠正 GSH 缺乏症可以恢复 NEFA 氧化并逆转这些缺陷。该提案将确定老年人中 GSH 缺乏与线粒体 NEFA 氧化受损之间的联系机制，并测试一种简单、安全、廉价的疗法，该疗法基于通过补充 GSH 前体氨基酸半胱氨酸和甘氨酸来改变饮食成分，以纠正 GSH 缺乏并恢复线粒体 NEFA 氧化。该提案还将测试GSH和NEFA氧化的恢复是否会导致老年人体内脂肪、肝内脂肪和肌细胞内脂肪的减少。